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This week the journal ‘Nature’ reports that the drug rapamycin, widely used to prevent transplant rejection and also currently in Phase II clinical trials for NF1 plexiform neurofibromas, may also have anti-aging properties. Mice taking the drug had extended lives of up to 14% versus those not taking drug. Intriguingly the longevity-promoting effect was seen even mice did not start taking rapamycin until they were relatively ‘elderly’ 600 days (equivalent to human aged 60). Its not yet clear if rapamycin might be prolonging life by preventing tumor growth or simply by slowing down the overall aging process. The study authors included researchers from University of Michigan, The Jackson Laboratory and the University of Texas. Media commentaries on the topic include an article in Thursday’s New York Times.

Tuesday morning included a session on new NF mouse models. Michel Kalamarides reported his mouse model of NF2 meningioma, in which these tumors can only develop if the NF2 gene is inactivated at a certain point in embryonic development.

Larry Sherman described his newly developed mouse model in which the schwannoma-related Brg1 gene is mutated.  Schwann cells derived from this mouse are hyperproliferative (divide too much) and make abnormally high levels of a growth factor BDNF; he is investigating whether this could potentially contribute to pain and a schwannomatosis phenotype.

Yuan Zhu presented a new mouse model that develops NF1 related of plexiform neurofibromas, dermal tumors and MPNSTs that are progressive and somewhat mimic the human state.  

The final session of the conference included presentations on new NF drug targets. Ronen Marmorstein is using structural design to optimize novel PAK inhibitors; this is partly in conjunction with Joe Kissil through a recently funded Children's Tumor Foundation DDI Award which will test them in animals with NF2 tumors.

Best 2009 Posters were a coup for Finland: Minja Laulajainen, University of Helsinki won Basic Science category for a merlin-focused study, and Lotta Alivuotila, University of Turku won Clinical category for a cognitive-focused NF1 study.  The 2009 NF Conference closed with the announcement of the 2011 NF Conference Chairs, Nancy Ratner and Michel Kalamarides. Before then of course, the 2010 NF Conference (‘NF- Back to the Future') - will take place in Baltimore, MD June 5-8, 2010 and will be co-chaired by Sue Huson and Filippo Giancotti.    

The Phase II clinical trial of AZD2171 for the treatment of plexiform neurofibromas or paraspinal neurofibromas needs a few final patients before closing recruitment. Patients should be over 18, not taking anti-convulsants and with normal heart, liver and kidney function.  Patients can be recruited through two sites: Mayo Clinic (Minneapolis) or  Harvard/MGH (Boston). Interested patients should contact one of the following: Carol Szumlanski, study coordinator -Phone: 507-294-1845 -Fax: 507-284-0079 -E-mail: Szumlanski.Carol@mayo.edu; Mayo site physician Dr. Dusica Babovic -Phone: 507-284-3215E-mail: dbabovic@mayo.edu;  or Harvard site physician Dr. Scott Plotkin splotkin@partners.org.

 

 

Monday kicked off with a session focused on cognitive deficits of NF1 tackling topics such as the challenges of translating learning disabilities mouse research findings into human trials, as well as molecular drug target updates. This included results from testing drugs in learning disabilities fruit fly models (a well received presentation from Foundation-funded Young Investigator Linnea Vose). It is emerging that the clinical features of NF1 cognitive deficits are driven by many things in the brain, including potentially the way that some of the neurons (nerve cells) develop and ‘wire up' in the first place. Learning disabilities continues to be a really exciting and fast moving area of NF1 research.

Among today's NF2 presentations Vijaya Ramesh reported that cell signaling element mTORC, long recognized as an important candidate drug target for the treatment of NF1 tumors, may also be a key drug target in NF2 tumors meningioma and vestibular schwannoma. For example rapamycin which targets mTORC was able to shrink meningioma tumor cells - which are overly large -  back to a more normal size.   

 The theme of the 2009 NF Conference is ‘New Frontiers', a nod to the remarkable progress made in NF research and the tackling of new challenges, such as sorting through emerging clinical trial options. However, some truly brand new frontiers remain. Schwannomatosis, the rarest form of NF, causes peripheral nerve tumors and unmanageable pain. A candidate gene for schwannomatosis, called INI1, was identified just two year ago, but many mysteries remain. Are NF2 mutations also involved in schwannomatosis? What about other genes?   Some of these issues were addressed in a session Monday morning. A major challenge to answering these questions is lack of patients, since many clinics will at most see only a handful of schwannomatosis patients, and a lot of the patients are being seen elsewhere perhaps in pain or plastic surgery clinics. For this reason the Children's Tumor Foundation is supporting a special initiative to establish a collaborative schwannomatosis database that will collect patient data from as many clinics as possible. On Monday evening representatives from about ten clinics US and international met to hammer out the questions this database must ask - these need to be detailed enough to make the data collected ‘mineable' (searchable, meaningful) to identify patients for follow up studies. Also though, at the first cut, the amount of data to be entered can't be too onerous as to put clinics off taking the time to enter it. The Foundation is providing initial funding to get this database up and running, but perhaps our most important role in this will be to encourage and drive as many clinics as possible to participate. We are very fortunate that this effort is being driven the enthusiastic Allan Belzberg and Amanda Bergner at Johns Hopkins and excited to see it move forward.   

 

 

The 2009 NF Conference got off to an exciting start Saturday with a full half day of presentations on ongoing or planned NF clinical trials. Roger Packer opened with an update on the Phase II NF Clinical Trials Consortium. The group has already fulfilled enrolment on the first NF1 trial - of rapamycin in plexiform tumors - and recently opened a trial to assess Lovastatin in NF1 learning disabilities. 

Next Consortium trials may include RAD001 (mTOR inhibitor) for optic pathway glioma as well as a bone trial. Scott Plotkin presented data from a new pilot trial to assess the blood vessel-targeted drug ranibizumab in NF1 dermal neurofibromas. Drug is injected directly into individual tumors and tumor size will be monitored. This trial is still in its earliest stages. Dr. Brigitte Widemann reported that by the end of 2009 another new NF1 trial will commence that combines two drugs - RAD001 and bevacizumab - for treatment of malignant peripheral nerve sheath tumors that have been resistant to other treatment. This combined therapy approach is, as I reported from ASCO, now being used in many tumor therapies.  

 In NF2 trials, Jaishri Blakeley reported on the Children's Tumor Foundation-funded Phase Zero trial to test lapatinib (kinase inhibitor) in vestibular schwannomas. This trial will be ready to enroll the first patient in July. Harry Miao reported on the new trial of PTC-299 (targeting blood vessel growth) in vestibular schwannomas also to commence soon.  

It is tremendous to see these clinical trial options opening up. Looking ahead, the Children's Tumor Foundation will endeavor to provide comprehensive information on all ongoing trials via our website to keep the community abreast of opportunities to participate.